Project Summary Cystic fibrosis (CF) is the most common autosomal recessive disease affecting Caucasian populations and causes progressive pulmonary decline and multi-organ disease leading to premature death. Cystic fibrosis- related diabetes (CFRD) affects up to half of adults with CF. Development of CFRD is associated with clinical deterioration including decline in pulmonary function, compromised nutritional status, and increased mortality. Insulin is the only recommended treatment for CFRD and has been demonstrated to improve clinical status and decrease mortality. Patients with CF already carry a significant medical burden managing the pulmonary manifestations of their disease, and the additional onus of frequent blood sugar monitoring and insulin injections that accompanies CFRD often leads to a decline in quality of life and non-adherence. One of the most promising strategies to improve glycemic regulation in people with type 1 diabetes (T1D) is automation of glycemic regulation with artificial pancreas (AP) devices. We have tested an AP device called the bionic pancreas extensively in subjects with T1D and have shown that it simultaneously reduces both mean glucose and hypoglycemia while reducing the work required for diabetes management and improving quality of life. There are several unique features of the bionic pancreas that make it ideally suited among AP systems for use in the CFRD population. The bionic pancreas rapidly and automatically adapts to a wide range of insulin needs, making it well suited to address fluctuations in insulin requirements of those with CFRD that occur during acute CF exacerbations and treatment with glucocorticoids. In addition, it is not necessary to carbohydrate count or inform the bionic pancreas when a meal is going to be eaten to achieve good glycemic control, which will be particularly useful for patients with CF who require frequent high calorie, high carbohydrate meals and snacks to maintain an adequate nutritional status. Moreover, the bihormonal configuration of the bionic pancreas, which can use micro-dose glucagon to prevent hypoglycemia when suspension of insulin delivery is insufficient, may be particularly useful for prevention of hypoglycemia in patients with CFRD, who are already at high risk for hypoglycemia due to pancreatic fibrosis leading to glucagon deficiency. In this proposal we will test the ability of the bionic pancreas to control blood glucose levels in subjects with CFRD with the following three aims: (1) We will test the short-term safety and efficacy of two configurations of the bionic pancreas, bihormonal (insulin/glucagon) and insulin-only, versus usual care in subjects with CFRD; (2) we will compare the long-term outpatient performance of the bionic pancreas versus usual care over a period of 6 months and look for preliminary evidence of improvement in non-glycemic outcomes such as pulmonary function, weight, and number of CF exacerbations; and (3) we will compare the bionic pancreas to usual glycemic inpatient management in patients with CFRD during hospitalizations for CF exacerbations, which are often associated with difficulty in glycemic management.